Insulin
Insulin is a hormone produced by the beta cells of the pancreas. Insulin delivered into the body through a syringe, insulin pen, pump or other delivery method is known as exogenous insulin. The role of exogenous insulin in treating diabetes mellitus was first discovered, and the substance refined, in 1921 at the University of Toronto by Sir Frederick Banting Sir Frederick Banting, and colleagues Best, Collip, and Mcleod. Commercial production began in 1923 at the newly formed Nordisk Insulin Labs (now Novo Nordisk) in Denmark, and at Eli Lilly and Co. in the USA. These are the various insulins discussed on this site. How it works InsulinInsulin-National Institutes of Health is necessary to enable the body to perform normallyinsulin is essential for many metabolic processes-ACVIM-Capsule Report. It controls the rate at which the body's cells can take in fuel (glucose). Without the insulin system, the body would burn fuel whenever it was available, instead of when it was most needed. It would also burn whatever is available for energy instead of the glucose it's meant to use. Our bodies normally are "fueled" by burning glucose; they are able to do this provided they have enough insulin (normally or by injection). When there's not enough insulin to allow the body to burn glucose for energy, it begins metabolizing fat to fuel its cells. In particular, the brain cannot go without energy even for a second, so it demands fat conversion to ketones when glucose energy is unavailableEnergy Metabolism Explained. Continuing this process using fat and ketones instead of glucose without sufficient insulin intervention is the path to ketoacidosis. With the insulin system working, insulin allows cells to use glucose found in the bloodstream, keeping them fed and preventing hyperglycemia. In the cells themselves, insulin aids in the anabolic (a positive, building or maintaining process) processes of turning glycogenDorlands Medical Dictionary-Glycogen Description/Definition stored in the liver and in muscles, into energy, and helps transform fatty acids and protein into forms both useful and necessary to the bodyThe Genetic Landscape of Diabetes-Drs. Dean & McIntyre. It complements or counter-acts the breaking-down the catabolic (breaking-down) Dorlands Medical Dictionary-Catabolic Definition body processes of gluconeogenesis, lipolysis, Wikipedia-Lipolysis Description (fat breakdown) and glycogenolysis (glycogen breakdown)Dorlands Medical Dictionary-Glycogen Breakdown ExplanationPediatric Oncall-Physiological Functions of Insulin. In diabetes, insulin is not produced in adequate quantities, or some of the insulin is not accepted by the receptors. While there is plenty of glucose within the system, the body's cells cannot accept it, and suffer what's called intracellular hypoglycemia-the cells cannot get the glucose they need without insulin. The hyperglycemia seen in blood glucose readings represents the glucose present in the body, which, without enough insulin, is unable to use it properly--it's called extracellular hyperglycemiaIntervet-Caninsulin UK-Diagram-Pathophysiology of Diabetes Mellitus-Insufficient Insulin--What Happens. Insulin secretion In those without diabetes, the healthy pancreas secretes insulin in pulses or spurts. Basal insulin secretion is a series of small pulses or spurts at a given rate day and night; these insulin pulses or spurts are to take care of the body's basic needs. When someone without diabetes eats a meal, the pancreas goes into higher gear, turning out larger quantities of post-prandial insulin to handle the additional glucose created by the foodIllustration of how much of the secreted insulin is basal (body needs) and how much is prandial (meal) insulin in a non-diabetic-Pediatric Oncall. This phase of insulin secretion is often referred to as the first phase, while the steady, slow basal rate is termed the second phaseInsulin Release-Wikipedia. Dogs who don't have diabetes have a similar insulin secreting pattern to people who don't have diabetes, with the same two phases intended for the same purposes as in humansManaging Diabetes Mellitus in Dogs-DVM 360-May 2008. It is this pattern that diabetics try to mimic as closely as possible; with Basal insulin injections for the body's needs without considering food and Bolus insulin injections to cover meals replacing the Basal and Postprandial insulin their bodies no longer produce or do not produce in sufficient quantityPostgraduate Medicine, White, et. al. 2003. The problem in Type 1 diabetes, which dogs have, is that the ability to signal the pancreas to produce insulin is missing; further, the damaged pancreatic beta cells are no longer capable of producing insulin to meet the body's needs for it. If the ability to signal for insulin production could be restored for someone with Type 1 diabetes, there would still be the problem of the pancreas beta cells being unable to supply the needed insulin. This is why insulin injections are necessary to replace the insulin the pancreas can no longer create. Oral medications are only able to help the system either produce more insulin or assist in the ability to use the insulin the pancreas is still able to produce. Those with Type 2 diabetes (which is what most cats have) are able to produce insulin, but the body's cells have lost the ability to use that insulin properly; this is the reason many Type 2 diabetics are able to use oral medications to control the disease.Better Medicine-E-Newsletter-June 2006Diabetes Mellitus-CVC Proceedings-Drugs other than insulin and insulin analogs used to treat diabetic human beings-DVM 360 2009 Insulin, then, in 10 words or less, is the hormone that lowers blood glucose and feeds the bodyIntervet-Caninsulin UK-Diagram of Insulin's Effects on the Body. And if you read no further, it would appear that as long as one has some insulin, either endogenous or exogenous, this is simple and everything will be fine. Kinetics & dynamics When reading various medical literature about insulin and its actions, one often sees the terms kinetics and dynamics used. Knowing what each means in terms of blood glucose can help you understand where it applies to you or your pet. Insulin Kinetics refers to the time when an insulin can be measured in the bloodstream. It's important to understand that even though it's "officially" made its way there, the insulin has not yet done so in sufficient quantity to effectively begin to lower blood glucoseAbsorption rates of subcutaneously injected insulin in the dog as calculated from the plasma insulin levels Diabetologia. 1983Endotext.org-Pharmacokinetics vs Pharmacodynamics. Insulin Dynamics is the point where it has an effect on blood glucose levelsDiabetesnet.com-Insulin Kinetics & DynamicsEndotext.org-Pharmacokinetics vs Pharmacodynamics. The dotted line shows insulin entering the bloodstream (kinetics). The bold line (dynamics) illustrates the insulin at the point where blood glucose is lowered by it. A good illustration of kinetics and dynamics is having a headache and taking an aspirin for it. You will get relief after the aspirin's level in your system has reached the dynamic stage. While it is in the kinetic one, you are still waiting for headache relief. Counterpoints to insulin There are other hormones present and also necessary to the body, which do the exact opposite of insulin--raising blood glucose levelsElmhurst College-Carbohydrate Hormone Control. Cortisol, growth hormone, adrenalin AKA epinephrine, glucagon, progesteroneExplanation of Progesterone's Functions-Veterinary Partner and thyroid hormone are considered counterregulatory hormonesCounter-Regulatory Hormones as far as diabetes and blood glucose levels are concerned. They need just as much consideration as insulin, because changes in their bloodstream levels can mean a possible interference with insulin, or a need for more of it. These changes can occur normally within the body to supply extra fuel when needed, or as symptoms of a disease state (Acromegaly=too much growth hormone, Cushing's disease=too much cortisol/cortisone, Hyperthyroidism=too much thyroid hormone, Hypothyroidism=too little thyroid hormone, Addison's disease=too little cortisol/cortisone ), or as a result of other medications, such as steroids. The counter-regulatory hormones such as adrenalin/epinephrine, glucagon and cortisol/cortisone are released to provide extra energy to the body in various circumstances, or if the body believes it's threatened with hypoglycemia. In some cases this is part of the body's "self-defense" mechanism to counter the effects of too much insulin. So there's more than just insulin one needs to think about. It's vital to life whether enough is produced by the body or whether it's injected. The other hormones are also vital to the body and being able to understand how the various hormones react or interact with each other is very helpful in understanding and successfully controlling diabetes. Strength The strength of an insulin is measured in International Units (IUs) of insulin per millilitre (ml). The two most common strengths used in pets are U40 (40 units insulin per ml) and U100 (100 units insulin per ml). U100 insulins are developed primarily for use in humans, although they are commonly used in pets. U40 insulins were commonly available in the US until the 1980's, along with the now-standard U100 strength. They are still available in some countries, but have been phased out in many, in favor of U100. For many years, insulin was produced in varying strengthsInsulin by Connaught 10 units 5 c.c. vial-10 units per c.c. 1923Lilly Iletin--1922--20 units in 5 ccIletin Vial and 2 Cartons-1923. Carton on Right is U20-U40 Carton is on LeftCloser Look at Iletin 1923 Vial U40Accuracy of Dosing U40 Insulin Register Free to View insulins are able to be drawn and dispensed in smaller doses (less than 5 units) with much greater accuracy than their U100 counterparts. This makes them advantageous for use in treating both children and pets, who both have smaller bodies and smaller insulin requirements than adult humans. U40 insulin has its advantages for more than children and pets. Less strength=speed The hexamers of insulin tend to associate with each other (stay together) when coming in contact with zinc in the bloodstreamIslets of Hope-Insulin; they cannot be readily absorbed while they remain this way; this is also how endogenous insulin is stored in the bodies of those who don't have diabetes--in hexamer formWikipedia-Insulin. Diluting insulin into U40 strength forces them into dissociating (staying apart from each other, and becoming dimers and monomers that can be used by the body), which means they are absorbedComparison of U100 and U40 Insulins-PubMedType 1 Diabetes Mellitus & Use of Flexible Insulin Regimens--Hirsch-American Family Physician-1999 better and more rapidly. An easy way to visualize this might be to think of a whole pie, slicing it into 6 pieces, then putting each piece on a separate plate. The pie can't be eaten until it's cut and everyone has a piece on his or her plate. While the body stores insulin in hexamer formWikipedia-Insulin, a normally working pancreas secretes insulin in monomer form, so there's no formation of hexamers by self-association and nothing to break down; the monomer insulin is ready to workChemistry and Pharmacology of Therapeutic Insulin Preparations, Abrams-Ogg, ACVIM 2007. This study compares the absorption rate of U100 and U40 insulins.Absorption Comparison--U40 & U100 Insulins-PubMed. The findings show U100 insulin to be significantly slower acting than U40 because it has a slower absorption rate. (Note the same study is available through a URL from DiabetesCopy of Reference 9 in ADA's Diabetes Care Publication Care--a publication of the American Diabetes Association.) From 30-40 minutes after injection, U40 insulin produces a 20% higher insulin level in the body than the identical amount of U100 insulin injected at the same time. U40 insulin often has a faster onset then does U100 insulinInsulin-Dependent Diabetes--Dr. Ragnar Hanas U40Comparison of U40, U100 and Rapid-Acting Insulin Lispro-PubMed insulin was also the subject of another 1998 study. This one compared it to both U100 insulin and the rapid-acting analog insulin Lispro (The only one marketed at the time.) Insulin lispro, known as Humalog, was found to be only slightly more rapidly absorbed than U40 non-analog insulin. The rapid-acting analog insulins such as Humalog, Novolog, NovoRapid and Apidra have amino acid sequences which are altered to prevent the insulin hexamers from remaining together in self-association. Diluting insulin from U100 strength also prevents this self-associationSubcutaneous Absorption of Insulin in Insulin-Dependent Diabetic Patients. Influence of Species, Physico-chemical Properties of Insulin and Physiological Factors-PubMed-Danish Medical Bulletin 1991. More strength=duration It is also possible to delay the absorption of an insulin by increasing the strength of its concentration. U500 insulinResource Guide-2005-American Diabetes Association, which is five times more concentrated than U100, has been available through both Lilly and Novo Nordisk (Note: Their similar product is U400 strength insulinUse of U500 Insulin in Patients With Extreme Insulin Resistance-Diabetes Care-ADA-2005) by special order for many yearsDiabetes Forecast-ADA,2006-Page 4. The insulin's main use is for people with extreme Insulin resistance, and is commercially available only in R/Neutral type. Though it is R/Neutral-type insulin, U400 & U500 insulinsDiabetes Monitor September 2008 have a pharmacokinetic profile more like NPH insulin than U100 R/NeutralDiabetes-World Mailing List Web Site-Questions About InsulinU-500 Insulin-Diabetes Spectrum,March 20, 2009. Since there are no additives such as suspensions to alter R/Neutral insulin's action, the strength of the insulin formula hinders its breakdown into dimers and monomers, thus making it much slower-absorbed than U100 and lesser strength insulinsFive Fold Increase of Insulin Concentration Delays the Absorption of Human Insulin Injections in Pigs-Diabetes Research & Clinical Practice-2000Use of U500 R Insulin by Continuous Insulin Infusion (Insulin Pump)in Patients With Type 2 Diabetes & Severe Insulin Resistance Endocrine Practice-2006Humulin R-U500 Patient Leaflet. In cases of severe insulin resistance, using a much higher concentration of insulin appears to "negate" the effects of immune-related insulin resistance. The studies at the link below shows that there was no difference regarding antibodies when these patients were transferred from Iletin II NPH at U100 strength to a form of Iletin II R at U500 strength. However, the stronger insulin reduced their insulin needs from 33-75%U500 Insulin in the Treatment of Antibody-Mediated Insulin Resistance-Annals of Internal Medicine-1981Enhanced Efficacy of U500 Insulin in the Treatment of Insulin Resistance Caused by Target Tissue Insensitivity-American Journal of Medicine-1984. Types by length of action Insulins are categorized first by length of action, then by origin and by suspension. The four durations areRxEd.org-Insulin Therapy: The usual times for onset, peak, and duration are found with the information for the insulin itself, but they also depend on the species, the suspension, and the individual. So the times found hereInsulin Activity Profiles-HealthLink are average for humans and dogs. This insulin chartTime Activity Profiles Insulin Chart--Dogs and Cats-Newman Veterinary is a bit dated, but seems to be a good guide to onset, maximum effect (peak) and duration. Types by origin Porcine insulin is identical to canine. Bovine insulin is similar to felineFeline Insulin Sequence-Science Direct, differing by only a single amino acid in position 18. (Mnemonic device: pi'G' = do'G', 'C'ow = 'C'at). Both differ in up to four amino acids (positions 8, 10, 18, 30) from natural human insulin.Insulin Amino Acid Sequences-Petdiabetes.org Porcine (pig) and bovine (cow) insulins can be combined to produce a "blended" insulin (such as Iletin I (beef/pork) and PZI Vet). Genetically-engineered artificial insulins with different amino acid composition such as Lantus, Levemir, Humalog, Novolog, and Apidra, are known as analog insulins. Origin, species, or source is very important as it directly affects the absorption, peak and duration of an insulinDiabetes Forecast-ADA, 2006-Page 3 Insulins differ by species. Most commonly available types are: Types by suspension The suspension (liquid the insulin is suspended in) is the key to its activity over time. Typical suspensions are Isophane: (NPH, Mixed), Zinc: (Lente, semilente, Ultralente) and Protamine Zinc: (PZI). In general, all insulins with the same suspension will have a similar time activity profile and behave similarly. In non-analog insulins, it is the suspension that makes intermediate and long-acting types work longer than R/neutral. Guidance on use See injecting insulin, resuspending insulin, drawing insulin, diluting insulin, combining insulin, combining insulin tutorial and insulin use tips. For dosage see regulation and insulin starting doses. For syringe information see syringe and syringe parts. Note that any insulin, given in overdose, can lead to hypoglycemia and coma or death. See avoiding hypos. For basic insulin use terms, see Onset, Peak, Nadir and Duration. For advanced use see also basal, bolus, and corrective insulin. For what can go wrong with insulin see absorption, and regulation difficulties, especially the Insulin problems section. Before each use, take a moment to inspect the insulin prior to drawing it into the syringe; clear insulins should appear not discolored and clear; suspended insulins should be uniform in their cloudinessRxEd.org-Insulin Therapy-Stability & Storage. If you made a mistake and forgot to put the insulin back into the refrigerator, even for several hours, there should be no problem. Many keep their insulin (see instructions for your brand) at room temperature all the timeFAQs.org-Travelling With Insulin. When comparing it to insulin which is in the fridge except when used, it may be more likely to have slight potency loss. When a vial has been left out of the refrigerator for some time, it needs to be monitored for any signs of frostingInsulin Update-storage of insulin; in the photo, the vial on the left is an example of frosting. If the insulin was exposed to heat or direct light for a while when it was out of the refrigerator, or shaken vigorously or dropped a long way, the best thing to do would be to start with a new vial Tips on Caring for Diabetic Pets-Diabetic-help.com. References More Information *Diabetes control in Siberian Husky-Vet Info.com Case details about using R/neutral and/or mixed insulins in dogs. *More details on insulin types for animal use-Elephantcare.org *More general insulin information-Endotext.org Good illustrations and charts for seeing where bovine and porcine insulins differ from human insulin and how analog insulins Lantus (insulin glargine), Novolog (insulin aspart), and Humalog (insulin lispro) have been altered to produce their respective effects. Some absorption discussion related to humans, some of which is relevant to animals, as absorption is an important factor in how the insulin is used for all with diabetes. Time activity profiles for everything except Levemir and any PZI. Aspart/Lispro chart would be applicable for the new Aventis Apidra, as it is also a rapid-acting insulin designed for bolus in humans. *The History of Insulin *The Discovery of Insulin *The Discovery and EarlyDevelopment of Insulin--University of Toronto *All About Insulin In Depth-In Chem *Time Activity Profile Tables for human approved insulins sold outside of North America *A chart of the variations in amino acid sequence on the A and B chains of different species-Diabetes in Pets. *Dr. Ragnar Hanas is a Swedish pediatrician whose book about Insulin-Dependent Diabetes is clearly written and easy to understand. Unlike many doctors, you feel she's talking with you and not down to you. Even though it was written in 1999 and insulins Lantus and Levemir were not yet marketed, the explanations are classic. She intended it for explaining human diabetes, but there is much we can gain from it too. The link is to a chapter she graciously donated to Children With Diabetes. *Click Here To View Time Activity Profiles of Lilly Insulins in humans and dogs *Health Canada--Insulin Comparison Chart--All But Levemir & Apidra *Health Canada--Intro to Diabetes and Insulin *Insulin Synthesis & Secretion--CSU Veterinary School of Medicine *Physiologic Effects of Insulin--CSU Veterinary School of Medicine *Physiological Effects of Insulin-Rnceus.com *NetDoctor.co.UK List of Insulins in the UK *Type I Diabetes and Insulin Therapy Nursing Clinics of North Americs-Hirsch-Farkas-Hirsch 1993 *OSU Endocrinology Symposium 2006-Selecting an Insulin for Treatment of Diabetes Mellitus in Dogs & Cats-Nelson-Page 39 *Switching to Another Insulin: What & How-North American Veterinary Conference 2006 *Evaluating Insulins for Companion Animals Abrams-Ogg ACVIM 2007 *Clinical Chemistry-Hormones Which Raise or Lower Blood Glucose *Insulin and Glucagon Tutorial and Animation *NACDS-Insulin Chart-Page 2 *Variability of Insulin Action-Does it Matter-Insulin Journal 2008 *Successful intensive insulin treatment of type 1 diabetic dogs leads to restoration of peripheral leukocyte insulin signaling gene expression and enzyme activities Journal of Veterinary Medical Science 2009 *Lente Insulins-Injectable Suspensions-West Virginia University College of Pharmacy-2009 Online videos *Short Movie Showing Effects of Insulin-Columbia University Category:Insulins Category:Treatments Category:Supplies Category:Regulation Category:Content